Viruses are a problem across the world, causing many of the diseases that afflict individuals today. Virus infections both in man and in animals have long presented a serious problem to which no wholly satisfactory answer has been found.
Some viral infections may be due to herpes infections. The herpesviruses are classified as, e.g., herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), roseolovirus or rhadinovirus.
Herpes simplex viruses (HSV) type 1 and type 2 are double stranded DNA viruses. The clinical entities attributable to HSV-1 include the following: (1) Acute herpetic gingivostomatitis which occurs mostly in small children; (2) Eczema herpeticum-Kaposi's varicelliform eruption which can sometimes be fatal; (3) Keratoconjunctivitis infection of the eye, with recurrent infection, which can lead to permanent opacification and blindness; (4) Herpes encephalitis which carries a high mortality rate and the survivors often have residual neurological defects; and (5) Herpes labilis, which present as cold sores and are most common recurrent disease in the form of oral lesions.
HSV-2 is implicated in the following: (1) Genital herpes or herpes progenitalis, which is characterized by vesiculoulcerative lesions of the penis or the cervix, vulva and vagina; (2) Neonatal herpes is a form of herpes that can be transmitted to the newborn during birth by contact with herpetic lesions in the birth canal if the mother is infected with the virus and sometimes can produce permanent brain damage.
Varicella zoster virus is a double-stranded DNA virus and it is morphologically identical with herpes simplex viruses. It is a causative agent for shingles in adults which is characterized by an inflammatory reaction of the posterior nerve roots and ganglia, accompanied by the affected sensory nerves. Varicella zoster virus (VZV) infection results in chickenpox (varicella), which may rarely result in complications including encephalitis or pneumonia. Even when clinical symptoms of chickenpox have resolved, VZV remains dormant in the nervous system of the infected person (virus latency), in the trigeminal and dorsal root ganglia. In about 10-20% of cases, VZV reactivates later in life producing a disease known as herpes zoster or shingles. Serious complications of shingles include post-herpetic neuralgia, zoster multiplex, myelitis, herpes ophthalmicus, or zoster sine herpete.
The symptoms of EBV infection in children can be indistinguishable from the symptoms of other typical childhood illnesses. Individuals not infected as a child have a risk of being infected during adolescence or young adulthood, which often causes infectious mononucleosis (mono). Diseases caused by EBV are particularly common among people with reduced immunity. EBV is associated with a tumor often found in organ transplant patients, which is referred to as post-transplant lymphoproliferative disease.
Typical antiviral medications used against herpes viruses work by interfering with viral replication, effectively slowing the replication rate of the virus and providing a greater opportunity for the immune response to intervene. Current treatments for human herpesviruses include acyclovir, cidofovir, famciclovir, doxorubicin and other pharmaceuticals. Moreover, amino purine derivatives have been disclosed in U.S. Pat. No. 3,758,684 to treat DNA virus infections and U.S. Pat. No. 7,628,993 covers DNA vaccines targeting a specific HSV-2 protein. U.S. Pat. No. 6,337,074 discloses peptides which disrupting the association of two viral proteins required for DNA replication in herpesviruses. U.S. Pat. No. 7,399,825 discloses peptides which inhibit infectivity of DNA viruses.
The vaccine Herpevac against HSV-2 has only been shown to be effective for women who have never been exposed to HSV-1. Overall, the vaccine is approximately 48% effective in preventing HSV-2 seropositivity and about 78% effective in preventing symptomatic HSV-2. During initial trials, the vaccine did not exhibit any evidence of preventing HSV-2 in males.
U.S. Pat. No. 7,611,704 covers compositions and methods of treating virus infections using Bavituximab and similar antibodies. Bavituximab is a PS-targeting antibody, the antibody's binding to phospholipids alerts the body's immune system to attack the tumor endothelial cells, thrombosing the tumor's vascular network and/or attacking free floating virally infected and metastatic cells while potentially minimizing side effects in healthy tissues.
Antiviral medications can reduce the frequency, duration, and severity of outbreaks. However, these infections are difficult to treat, treatments are not effective for all patients and there is no cure that can eradicate herpes virus from the body. Therefore, currently, there is no effective treatment against the infections caused by human herpesviruses and improved methods for treatment are being sought. Furthermore, viruses can become resistant to current treatments so there is a need to find new antiviral agents having new mechanisms of action.
Recent work published in Nature Medicine found that the host enzyme LSD1 interacts with a key host protein (HCF-1) that the herpesviruses require to infect host cells. Herpes viruses lack their own RNA polymerase and require the use of a host. To prepare a host for viral gene transcription, α-herpesviruses need to increase methylation of histone H3Lys4 (H3K4) and decrease methylation of H3K9. Researchers reported in Nature Medicine that to decrease the methylation, the demethylase called lysine-specific demethylase-1 (LSD1) is required. LSD1 interacts with the host cell factor-1 (HCF-1) component of the histone methyltransferase complex. Moreover, blocking LSD1 activity using monoamine oxidase inhibitors (MAOIs), which are known to target LSD1, led to inhibition of viral gene transcription. Researchers noticed when levels of LSD 1 are reduced the corresponding levels of HSV and VZV mRNA and proteins decreased. This discovery suggest a new way to attack virus infections, inhibiting LSD1, the virus host's transcriptional machinery to produce viral mRNA is stopped, therefore decreasing the ability of α-herpesvirus to express the viral genes necessary to continue infection.
Lysine Specific Demethylase-1 (LSD1) has a fair degree of structural similarity, and amino acid identity/homology to monoamine oxidases. It was recently found that some compounds which target monoamine oxidase (MAO), also inhibit LSD 1 at clinically relevant concentrations (Lee et al. (2006) Chem. Biol. 13:563-567, Schmidt et al. (2007) Biochemistry 46(14)4408-4416) and Gooden et al. (2008) Bioorg. Med. Chem. Let. 18:3047-3051).
WO 2010/011845 discloses inhibitors of LSD 1 and/or MAOs inhibitors for treating or preventing viral infections. However, the disclosed inhibitors are known to inhibit MAO enzymes more strongly than LSD 1 and moreover, they indistinctly inhibited MAOs. Since MAO-A inhibitors can cause dangerous side-effects (see e.g., Yoshida et al. (2004) Bioorg. Med. Chem. 12(10):2645-2652; Hruschka et al. (2008) Biorg Med. Chem. (16):7148-7166; Folks et al. (1983) J. Clin. Psychopharmacol. (3)249; and Youdim et al. (1983) Mod. Probl. Pharmacopsychiatry (19):63) selective LSD1/MAO-B dual inhibitors present an important advantage.
Furthermore, most of the LSD1 selective inhibitors of the prior art Ki (IC50) parameters higher than 1 μM for LSD1. Without intending being bound by any theory, the inventors believe that more efficient selective LSD1 inhibitors can have better results when used as antiviral, which could implicate lower doses and less side effects. Additional dual LSD1/MAO-B inhibitors can avoid the side-effects associated with inhibition of MAO-A.
Although the foregoing methods have advanced the art of antiviral treatment, the development of additional or alternative targeting therapies is still sought. The development of new drugs that prevent or treat viral infection of a host by inhibiting novel targets, particularly those which selectively inhibit LSD1 and LSD 1/MAO-B is an importance advance. In view of the good LSD1 and LSD1/MAO-B-selective inhibition of the novel “cyclopropylamine acetamide” derivatives and “cyclopropylamine” derivatives, these represent a new class of compounds for preventing or treating viral infections with novel mechanisms of action.